Borna disease virus (BDV) is a neurotropic virus that causes immune- mediated neurologic disease. Originally considered to be a pathogen only in horses and sheep in central Europe, evidence of natural infection has now been found in various domestic animals in Africa, greater Europe and North America. Birds, rodents and primates are readily infected experimentally and show characteristic disturbances in behavior. Antibodies reactive with BDV proteins have been found in individuals with central nervous system (CNS) diseases including HIV-encephalopathy, depression and schizophrenia. Whether this immunoreactivity is due to infection with a BDV-like agent or cross reactivity with host cell components is not known. BDV appears to be only remotely related to known viruses. It has a negative-polarity RNA genome and an unusual nuclear strategy for replication and transcription. It causes no overt tissue damage in the absence of host immune response, grows only to low titers, has a broad species range and unique tropism for specific CNS regions. These features suggest that BDV could be important as an emerging pathogen, as a probe for studying the pathogenesis of selected CNS diseases and as a tool for neurobiology. In the long term, it should be possible to exploit BDV neurotropism by using cloned components of the virus to target delivery of drugs or genes to specific cells and regions in the CNS for treatment of human diseases. The broad objectives of this project will be to: 1.) characterize the biology of this novel infectious agent and the molecular basis for its neurotropism; 2.) define the epidemiology and significance of immunoreactivity to BDV proteins in human neurologic and psychiatric diseases. Specific aims for the proposed project period will include, Molecular biology of BDV: i.) clone and analyze genomic and subgenomic RNAs; ii.) define the time course of RNA and protein synthesis; iii.) investigate the role of host factors in replication and transcription (and tissue tropism); iv.) establish an in vitro transcription/translation system; v.) study a virion surface protein that is likely to function in host cell recognition. Immunoreactivity to BDV in Human Disease: i.) determine the prevalence and time course of immunoreactivity to BDV proteins in human subjects (individuals infected with HIV followed for progression to neurologic disease, schizophrenics and controls); ii.) map the epitopes detected by human sera; iii.) investigate the presence of BDV nucleic acids in human tissues and cerebrospinal fluids; iv.) in the event that BDV infection cannot be implicated as the basis for immunoreactivity, identify and characterize the basis for cross reactivity to BDV proteins.